1. Technical Field
The present disclosure generally relates to a chemistry matrix and methods for measuring the presence and/or concentration of an analyte in a biological fluid. More specifically, but not exclusively, the present disclosure relates to a chemistry matrix and methods that increase the analyte specificity when measuring analyte with an electrochemical biosensor in the presence of interfering substances. As used herein, the term “chemistry matrix” refers to a physical region containing at least one chemical substance capable of reacting with an analyte.
2. Description of Related Art
Measuring the concentration of substances, particularly in the presence of other confounding substances and under varied conditions, is important in many fields. For example, the measurement of glucose in bodily fluids, such as blood, under varied conditions and in the presence of interfering substances, is crucial to the effective treatment of diabetes. The failure to properly control blood glucose levels can produce extreme complications, including blindness and loss of circulation in the extremities, which can ultimately deprive the diabetic of use of his or her fingers, hands, feet, etc.
Test strips are often used to measure the presence and/or concentration of selected analytes in test samples. For example, a variety of test strips are used to measure glucose concentrations in blood to monitor the blood sugar level of people with diabetes. These test strips include a reaction chamber into which a reagent composition has been deposited. Current trends in test strips require smaller test samples and faster test analysis times. A significant benefit is provided to the patient when using smaller test samples, which can be obtained from less sensitive areas of the body, such as the forearm. Additionally, faster and more accurate test times provide added convenience and better control of the patient's blood sugar level.
Several methods are known for measuring the concentration of analytes, such as, for example, glucose, in a blood sample. Such methods typically fall into one of two categories: optical methods and electrochemical methods. Optical methods generally involve reflectance or absorbance spectroscopy to observe the spectrum shift in a reagent. Such shifts are caused by a chemical reaction that produces a color change indicative of the concentration of the analyte. Electrochemical methods generally involve amperometric, coulometric, potentiometric, and/or conductive responses indicative of the concentration of the analyte. See, for example, U.S. Pat. No. 4,233,029 to Columbus; U.S. Pat. No. 4,225,410 to Pace; U.S. Pat. No. 4,323,536 to Columbus; U.S. Pat. No. 4,008,448 to Muggli; U.S. Pat. No. 4,654,197 to Lilja et al.; U.S. Pat. No. 5,108,564 to Szuminsky et al.; U.S. Pat. No. 5,120,420 to Nankai et al.; U.S. Pat. No. 5,128,015 to Szuminsky et al.; U.S. Pat. No. 5,243,516 to White; U.S. Pat. No. 5,437,999 to Diebold et al.; U.S. Pat. No. 5,288,636 to Pollmann et al.; U.S. Pat. No. 5,628,890 to Carter et al.; U.S. Pat. No. 5,682,884 to Hill et al.; U.S. Pat. No. 5,727,548 to Hill et al.; U.S. Pat. No. 5,997,817 to Crismore et al.; U.S. Pat. No. 6,004,441 to Fujiwara et al.; U.S. Pat. No. 4,919,770 to Priedel et al.; and U.S. Pat. No. 6,054,039 to Shieh, which are hereby incorporated by reference in their entireties. Electrochemical methods typically use blood glucose meters (but not always) to measure the electrochemical response of a blood sample in the presence of a reagent. The reagent reacts with the glucose to produce charge carriers that are not otherwise present in blood. Consequently, the electrochemical response of the blood in the presence of a given signal is intended to be primarily dependent upon the concentration of blood glucose. Typical reagents used in electrochemical blood glucose meters are disclosed in U.S. Pat. Nos. 5,997,817, 5,122,244, and 5,286,362, which are hereby incorporated by reference in their entireties.
A number of error sources can create inaccurate results when measuring analyte levels in body fluid. Sometimes harsh conditions to which the sensor is exposed worsen the accuracy of the sensor. Occasionally, the sensor can experience harmful conditions, often termed “strip rotting” or “vial abuse”, which refers to when the sensors during storage are abused and exposed to detrimental conditions, such as excessive heat, light, and/or moisture. This exposure to excessive heat and/or moisture can result in slowing of the reaction times due to loss of enzyme activity.
In the past, these issues have been avoided by using enzymes that have very fast reaction times and high specific activities with the analyte being measured. By utilizing enzymes with these particular characteristics, reactions having high and similar levels of completion under all test conditions, such as at various temperatures and hematocrit levels, can be achieved. However, as a practical matter, enzymes usually cannot be incorporated with high enough amounts into the sensor without causing a significant loss in performance of the sensor. In addition, enzymes of high specific activities are not always desirable for all analytes. For example, such systems for determining glucose levels still fail to address the need of being free from the effects of interferents, such as maltose, galactose, xylose, and the like, which can create inaccurate readings.
For example, patients undergoing peritoneal dialysis or IGG therapy can experience high levels of maltose in their blood, which can interfere with accurate blood glucose readings. Therefore, interference from maltose can be a significant problem. As an illustration, Abbott Laboratories' Freeystyle® blood glucose monitoring system employs a glucose-dye-oxidoreductase (GlucDOR) enzyme in conjunction with a coulometric technique with a variable test time. However, such a system is still clinically unacceptable due to interference from maltose, and, as a practical matter, the use of coulometry, as currently practiced, has a number of significant drawbacks. Further, attempts have been made to minimize the maltose interference effect by cloning new GlucDOR enzymes with a greater specificity to glucose. However, progress has not resulted in a feasible solution.
In still yet another example, Abbott Laboratories' PCx/TrueMeasure™ system utilizes amperometry coupled with a Nicotinamide Adenine Dinucleotide (NAD)-dependent Glucose Dehydrogenase enzyme (GDH/NAD) to provide a system substantially free from maltose interference. However, the amperometric system can provide inaccurate readings because of blood oxygen level (pO2) interference, an effect that causes readings of glucose levels to vary due to a variety of factors including where the sample is taken. For example, blood oxygen levels can vary substantially depending on whether the sample is capillary, venous, or arterial blood. Consequently, to minimize oxygen interference, a user of this system must indicate the source or nature of the blood sample prior to sampling. As can be appreciated, requiring the user to enter information regarding the blood sample provides an additional source of error if the information is erroneously entered by the user.
In addition to slowing enzyme activity, vial abuse can also result in an increase of background current, sometimes referred to as “blank current”, when readings are taken. A variety of sources for background or blank current exist. For instance, it is desirable that mediators, which are used to transfer electrons from the enzyme to the electrode, be in an oxidized state before the sensor is used. Over time the heat and/or humidity from the vial abuse will tend to reduce the mediator. If part of the mediator is in a reduced form before the sensor is used, a portion of the current will result from the working electrode oxidizing the reduced form of the mediator. The resulting background or blank current will tend to bias the mediator, which in turn can lead to inaccurate results. Other impurities in the reagent can also increase background or blank current problems.
Amperometric sensors have been proposed that use a “burn-off” approach to address the blank current problem. In this approach, two DC signals are applied to the sensor. The first DC signal, or burn-off signal, is used to consume or oxidize any species responsible for the blank current in the same diffusion layer that is later used to analyze the analyte. Afterwards, the second signal, or analysis signal, is used to analyze the analyte levels. Both the burn-off and analysis potentials have the same polarity. Although this burn-off technique reduces the effect of blank or background current, it does so at the expense of partially oxidizing (or reducing) the analyte to be measured, thereby reducing the noise-to-signal ratio of the sensor. Moreover, such techniques have failed to compensate for variations in reaction time caused by factors like temperature and enzymes with slow/variable reaction velocities, to name a few examples. In addition, the enzymes used in such sensors tend to be susceptible to maltose interference.
In view of the above, it is desirable for a biosensor utilized to measure an analyte (such as glucose) to have a chemistry matrix with increased specificity for the analyte, and to be capable of minimizing interferences resulting from fluctuations in oxygen levels and from interfering substances such as maltose. It is further desirable to provide a chemistry matrix that is photochemically stable.